Malaria remains a significant health threat to humans despite massive international attempts to eradicate the disease. Over 200 million people are said to have malaria and over one million deaths per year are associated with malaria in Africa alone. In many of the endemic areas, local supply of food is quite limited, a problem which is greatly aggravated by the presence of protozoal infections in cattle and other farm animals. Malaria is a disease of warm blooded animals caused by infection with a parasite of the genus Plasmodium. Four species, P. vivax, P. falciparum, P. malariae, and P. ovale, are known to infect humans. The parasite is transmitted to humans by the bite of Anopheles mosquitoes. Subsequent to mosquito bite, the parasite rapidly invades the blood cells of the victim and after a incubation period, generally lasting about 10 to 14 days, symptoms, consisting of chills, fever, headache, muscle pains, splenomegaly, and anemia, appear. This incubation period may be prolonged for many weeks and onset can be quite insidious. Red blood cells are at first altered and later destroyed by the infection.
Drug therapy utilizing quinine, chloroquine, amodiaquine, primaquine, and other agents has been the mainstay of therapy against malaria. However, drug-resistant strains of plasmodia have developed and in some cases strains are resistant to many or all of the current therapeutic agents. In particular, P. falciparum malaria is quite prone to exhibit single and even multiple drug-resistance. While new agents are continually developed and introduced, resistance to such new agents also quickly develops. For example mefloquine-resistant malaria was reported even before mefloquine licensure was completed. There is, thus, an urgent need for antimalarial agents which can be used in the treatment of drug-resistant malarial diseases.
Recently it was reported that imipramine and amitriptyline suppress weakly, P. falciparum growth., possibly by virtue of the ability of these agents to interfere with riboflavin metabolism. While scientifically interesting, the practical use of imipramine and amitriptyline in the treatment of malaria would seem unlikely because of the lethal concentrations required to produce the antimalarial effect in humans. While not practically useful in the treatment of non drug-resistant malaria, applicants have now discovered that desipramine, when administered in normal therapeutic doses in conjunction with standard antimalarial agents, is highly effective in treating drug-resistant malaria and is useful in the prophylaxis of drug-resistant malaria.